Alternative macrophage activation limits immunopathology

描述（由申请人提供）：巨噬细胞是异质性骨髓吞噬细胞，通过未解决的机制驱动宿主防御和伤口修复。本计画探讨肺部巨噬细胞生物学在寄生虫感染后的宿主免疫与组织修复的情形。全世界有超过10亿人感染寄生蠕虫，根据蠕虫的种类，感染者可能遭受不同程度的肺损伤。蠕虫感染个体的胸部X射线图像的历史数据显示，抗蠕虫治疗后组织损伤自发消退。我们的数据表明，肺巨噬细胞是必不可少的短暂性蠕虫引起的肺损伤。本次更新申请将确立肺巨噬细胞用于抑制病原体特异性炎症、促进上皮再形成和恢复肺气体交换功能的机制。我们将从基因上耗尽CD 68+组织巨噬细胞，监测血氧含量（SpO 2），并跟踪促炎性第2组先天淋巴细胞（ILC 2）和免疫抑制调节性T细胞群，以实现我们的项目目标。我们有证据表明，肺巨噬细胞耗竭导致ILC 2扩增增加，并降低受损肺组织中的白细胞介素10水平。此外，我们提供了巨噬细胞通过产生Wnt蛋白驱动上皮再形成的证据，Wnt蛋白是上皮细胞再生的既定介质。因此，我们的项目研究钩虫感染期间宿主保护性免疫的机制，作为了解可逆性肺损伤的替代。更清楚地了解感染后的肺修复对于数百万患有急性和慢性肺部疾病的人来说非常重要。到2020年，急性和慢性肺部疾病预计将成为美国第三大死亡原因。显然，非常需要了解炎症和修复是如何在肺道内调节的。因此，我们将测试肺巨噬细胞产生限制ILC 2扩增并促进调节性T细胞扩增的免疫抑制性细胞因子以及肺巨噬细胞通过Wnt 4a依赖性机制直接促进上皮再生的假设。该假设将在以下特定目的中进行测试：目的1将确定肺功能的修复和肺稳态的恢复是否需要肺巨噬细胞或ILC 2。目的2将确定肺巨噬细胞是否通过IL-10和/或TGF依赖性机制抑制ILC 2或诱导调节性T细胞扩增，目的3将鉴定负责巨噬细胞驱动的上皮再生的分子机制。这项工作的完成将提供一个更深入的了解感染诱导的炎症和肺组织再生是如何通过骨髓和淋巴谱系编排。

DESCRIPTION (provided by applicant): Macrophages are heterogeneous myeloid phagocytes that drive host defense and wound repair through unresolved mechanisms. This project investigates lung macrophage biology in the context of host immunity and tissue repair following parasitic helminth infection. More than one billion people worldwide are infected with parasitic helminthes and depending upon the worm species, infected individuals can suffer various degrees of lung injury. Historical data from chest x-ray images of worm-infected individuals revealed spontaneous resolution of tissue damage occurred following anti-helminthic therapy. Our data shows that lung macrophages are essential for the transient nature of helminth induced lung injury. This renewal application will establish the mechanism(s) used by lung macrophages to suppress pathogen-specific inflammation, facilitate re- epithelialization and restore lung gas exchange function. We will genetically deplete CD68+ tissue macrophages, monitor blood oxygen content (SpO2), and track both pro-inflammatory group 2 innate lymphoid cells (ILC2) and immunosuppressive regulatory T cell populations to achieve our project goals. We have evidence that lung macrophage depletion causes increased expansion of ILC2 and reduces interleukin 10 levels within injured lung tissue. Moreover, we provide evidence that macrophages drive re-epithelialization through producing Wnt proteins, which are established mediators of epithelial cell regeneration. Therefore, our project investigates mechanisms of host protective immunity during hookworm infection as a surrogate for understanding reversible lung injury. A clearer understanding of lung repair following infection is extremely important for millions of individuals suffering from acute and chronic forms of lung disease. Combined, acute and chronic lung diseases are predicted to be the 3rd leading cause of death within the United States by 2020. Clearly, there is a great need for understanding how inflammation and repair are regulated within the pulmonary tract. Therefore, we will test the hypothesis that lung macrophages produce immunosuppressive cytokines that limit ILC2 expansion and promote regulatory T cell expansion and also that lung macrophages directly promote epithelial regeneration via a Wnt4a-dependent mechanism. This hypothesis will be tested in the following specific aims: Aim 1 will determine whether repair of pulmonary function and restoration of lung homeostasis requires lung macrophages or ILC2. Aim 2 will determine whether lung macrophages suppress ILC2 or induce regulatory T cell expansion via IL-10 and/or TGF-dependent mechanisms and Aim 3 will identify the molecular mechanism(s) responsible for macrophage-driven epithelial regeneration. Completion of this work will provide a deeper understanding of how infection-induced inflammation and pulmonary tissue regeneration are orchestrated via myeloid and lymphoid lineages.